Pikromycin

Pikromycin
Names
IUPAC name
(3R,5R,6S,7S,9R,11E,13S,14R)-14-ethyl-13-hydroxy-3,5,7,9,13-pentamethyl-2,4,10-trioxooxacyclotetradec-11-en-6-yl 3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranoside
Other names
Picromycin
Identifiers
19721-56-3 YesY
ChEBI CHEBI:29665 N
ChemSpider 4445267 YesY
Jmol interactive 3D Image
PubChem 5282037
Properties
C28H47NO8
Molar mass 525.68 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Pikromycin was studied by Brokmann and Hekel in 1951 and was the first antibiotic macrolide to be isolated.[1] Pikromycin is synthesized through a type I polyketide synthase system in Streptomyces venezuelae, a species of Gram-positive bacterium in the Streptomyces genus.[2] Pikromycin is derived from narbonolide, a 14-membered ring macrolide. [3] Along with the narbonolide backbone, pikromycin includes a desosamine sugar and a hydroxyl group. Although Pikromycin is not a clinically useful antibiotic, it can be used as a raw material to synthesize antibiotic ketolide compounds such as ertythromycins and new epothilones. [4]

Biosynthesis

The pikromycin polyketide synthase of Streptomyces venezuelae contains four polypeptides: PikAI, PikAII, PikAIII, and PikAIV. These polypeptides contain a loading module, six extension molecules, and a thioesterase domain that that terminated the biosynthetic procedure. [5] Recently electron cryo-microscopy have been used to determine sub-nanometre-resolution three- dimensional reconstructions of a full-length PKS module from the bacterium Streptomyces venezuelae that revealed an unexpectedly different architecture. [6] In Figure 1, each circle corresponds to a PKS mutilifuctional protein, where ACP is acyl carrier protein, KS is keto-ACP synthase, KSQ is a keto-ACP synthase like domain, AT is acyltransferase, KR is keto ACP reductase, KR with cross is inactive KR, DH is hydroxyl-thioester dehydratase, ER is enoyl reductase, TEI is thioesterase domain I, TEII is type II thioesterase. [7] Des corresponds to the enzymes utilized in desosamine biosynthesis and transfer, which include DesI-DesVIII.

Figure 2 represents the desosamine deoxyamino sugar biosynthetic pathway. DesI-DesVI (des locus of pikromycin PKS) encodes all the enzymes needed to obtain TDP-desoamine from TDP-glucose. DesVII and DesVIII activities transfer desoamine to narbonolide and narbomycin is obtained. PikC cytochrome P450 hydrolase catalyzes the hydroxylation of narbomycin to obtain pikromycin. [8]

Figure 1: Domain organization of PKS for Narbonolide, a precursor of Pikromycin
Figure 2: Pikromycin Formation through the desosamine deoxyamino sugar biosynthetic pathway

See also

References

  1. ↑ Brockmann, H. and Henkel, W. (1951). "Pikromycin, ein bitter schmeckendes Antibioticum aus Actinomyceten". ntibiotica aus Actinomyceten 84: 184–288. doi:10.1002/cber.19510840306.
  2. ↑ Y. Xue and D. Sherman (2001). "Biosynthesis and Combinatorial Biosynthesis of Pikromycin-Related Macrolides in Streptomyces venezuelae". Metabolic Engineering 3: 15–26. doi:10.1006/mben.2000.0167.
  3. ↑ Maezawa, T. Hori, A. Kinumaki and M. Suzuki (1973). "Biological conversion of narbonolide to picromycin". The Journal of Antibiotics 26: 771–775. doi:10.7164/antibiotics.26.771. PMID 4792390.
  4. ↑ J.D. Kittendorf and D.H. Sherman (2009). "The Methymycin/Pikromycin Biosynthetic Pathway: A Model for Metabolic Diversity in Natural Product". Bioorg Med Chem 17: 2137–2146. doi:10.1016/j.bmc.2008.10.082.
  5. ↑ S. Guptaa, V. Lakshmanan, B.S. Kima, R. Fecik, and K. A. Reynolds (2008). "Generation of Novel Pikromycin Antibiotic Products Through Mutasynthesis". Chembiochem 10: 1609–1616. doi:10.1002/cbic.200700635.
  6. ↑ S. Dutta, J. R. Whicher, D. A. Hansen, W. A. Hale, J. A. Chemler, G. R. Congdon, A. R. H. Narayan, K. Håkansson, D. H. Sherman, J. L. Smith, G. Skiniotis (2014). "Structure of amodular polyketide synthase". Nature 510: 512–517. doi:10.1038/nature13423.
  7. ↑ D.L. Akey, J.D. Kittendorf, J.W. Giraldes, R.A. Fecik, D.H. Sherman, and J.L. Smith (2006). "Structural basis for macrolactonization by the pikromycin thioesterase.". Nature Chemical Biology 2: 537–542. doi:10.1038/nchembio824.
  8. ↑ Y. Xue and D. Sherman (2001). "Biosynthesis and Combinatorial Biosynthesis of Pikromycin-Related Macrolides in Streptomyces venezuelae". Metabolic Engineering 3: 15–26. doi:10.1006/mben.2000.0167.
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